1. Field of the Invention.
The invention relates to tyrosine kinase inhibitors of the bis-indolyl compound type, pharmaceuticals containing them and their use for the treatment of malignant and other diseases based on pathological cell proliferation.
2. Background Information
The activation of tyrosine-specific protein kinases is a key event in stimulation of the division of animal cells. Normally, this stimulation is effected by exogenous factors, e.g. growth factors, when the proliferation of a certain cell type is necessary for the overall function of a tissue or organ. In tumours, cell proliferation is also linked with the activity of tyrosine kinases. In tumour cells, however, an aberrant activity of kinases is often present, which is caused by overexpression, constitutively active kinase mutants or ectopic activity of growth factors. The PDGF receptor is one of the growth factors with relevance for human tumours. PDGF is one of the main mitogens in the serum and is present in high concentrations in blood platelets. Its most important function in the adult body is wound healing. An undesired activity of the PDGF receptor is involved in the proliferation of various tumours, e.g. gliomas, glioblastomas, sarcomas, mastocarcinomas, ovarian carcinomas and colonic carcinomas. An aberrant activation of the PDGF/PDGF receptor system also assumes a key position in pathological hyperproliferation of mesenchymal cells in the context of arteriosclerosis, restenosis after balloon angioplasty, arthritis and fibrotic diseases.
A few growth factor receptor tyrosine kinases, whose tyrosine kinase domains have high sequence homology to the tyrosine kinase domain of the PGDF receptors, are also of importance for the tumour process and pathological hyperproliferation. These include the receptors for the vascular endothelial cell growth factor (VEGF)KDR/Flk-1 and Flt-1 with great importance for tumour vascularization, Kit/SCF receptor, for which constitutively active versions were observed in carcinomas and Flk-2/Flt-3, a receptor involved in the proliferation of leukemia cells of various forms of disease. It can be expected that further members of this kinase family with relevance for pathological proliferation will be identified. In addition to mitogenic stimulation, the actions of the ligands of these receptors often also include the stimulation of cell migration, anti-apoptotic actions and effects on membrane transport systems for ions, water and chemical compounds. To a varying extent, uncontrolled effects of this type are also involved in the pathological process in tumours and other diseases.
Of the various possibilities for switching off the signal of receptor tyrosine kinases, the specific direct inhibition of the activity of the kinase is the most promising.
The invention is therefore aimed at creating compounds which are suitable as inhibitors of tyrosine kinases, in particular of the PDGF receptor tyrosine kinases and further, related tyrosine kinases such as KDR/Flk-1, Kit/SCF receptor and FLK/Flt-3. This object is achieved by the compounds of the general formula I according to the invention: 
in which Z is a group having the general formula (II) 
in which A can be nitrogen, oxygen or sulphur atoms and [sic] B, Bxe2x80x2 can be carbon, nitrogen, oxygen and sulphur atoms and the ring systems F and G independently of one another can be either saturated or unsaturated 5- and 6-membered rings,
X is a group having the general formula III or IV 
in which A has the same meaning as above, 1 and n can assume the numbers from 0 to 6, m the numbers 1 and 2, and R14 and R15 either together form an oxygen atom or R14 is a hydroxyl group and R15 is a hydrogen atom or R14 and R15 are hydrogen atoms and where R16 is a hydrogen atom, an alkyl or aryl radical, halogen-, amino-, or azido-substituted alkyl or aryl radical, an alkyloxymethyl or substituted alkyloxymethyl radical, R2 and R13 together from a linkage having the general formula V or VI 
where the dashed bond is a double or single bond, A and R16 have the same meaning as above and o can assume the numbers 1 and 2,
R2 and R13 are identical or different radicals of the general formula VII or hydrogen atoms, 
where the dashed bond is a double or single bond, A and R16 have the same meaning as above and R17 is a halogen atom or a radical of the general formulae [sic] VIII 
such that p can be=0, 1 or 2 (if p=0 then it is an acyclic primary amine and Y carries an additional hydrogen atom), Y can be a carbon, oxygen or nitrogen atom and if Y is a carbon or nitrogen atom, R18 is a hydrogen atom or an alkyl or aryl radical, substituted alkyl or aryl radical, saturated or unsaturated heterocycle, alkoxycarbonyl radical, aminocarbonylmethyl radical or substituted aminocarbonylmethyl radical,
R2 and R13 together form a linkage having the general formula IX or X 
where W is either a carbon or a nitrogen atom, q can assume a value between 0 and 6 and R19 and R20 can be hydrogen atoms, alkyl radicals or substituted alkyl radicals,
in which R1 and R7 are identical or different and are hydrogen atoms, alkyl or aminoalkyl radicals, phenylsulphonyl radicals, alkylsilylmethoxymethyl radicals, a sugar or substituted sugar,
where R3, R4, R5, R6, R8, R9, R10 and R11 are identical or different and in each case is a hydrogen atom, an alkoxy-, amino-, halogen-, cycloalkyl-, cyclohetero- alkyl-, aryl- or heteroaryl-substituted alkyl, alkoxy or alkoxymethyl group, nitro group, a halogen atom or an O-alkoxy group of the general form xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94R21, where R21 are [sic] an alkoxy-, amino-, halogen-, cycloalkyl-, cycloheteroalkyl-, aryl- or heteroaryl-substituted alkyl, alkoxy or alkoxymethyl group.
Preferred compounds according to the invention are those having the above general formulae [sic] I, in which Z is a group having the general formula II and X is a group having the general formula III, R2 and R13 are hydrogen atoms, A is a nitrogen atom and B is a nitrogen, oxygen or sulphur atom and R3, R4, R5, R6, R7, R8, R9, R10, R, R14 and R15 have the same meaning as above, where these compounds correspond to the following formula XI: 
Particularly preferred compounds are those of the formula XI in which R14 and R15 together form an oxygen atom.
Additionally preferred compounds according to the invention are those having the above general formula I in which Z is a group having the general formula II an d X is a group having the general formula III, R1 and R 2 are hydrogen atoms, A and B are nitrogen atoms, and R1, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R16 have the same meaning as above, where these compounds correspond to the following formula XII: 
Additionally preferred compounds according to the invention are those having the general formulae XIII and XIV below 
in which n is the numbers 3, 4, 5, 8 or 12, q is the numbers 0, 1, 2, 3, 5 or 6, R19, R20 are hydrogen atoms or alkyl groups and R1, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R16 are identical or different and have the same meaning as above.
Additionally preferred compounds according to the invention are those having the following general formula XV 
in which n is the numbers 1, 2 or 3, R16 is a hydrogen atom or an alkyl group and R1, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R16 are identical or different and have the same meaning as above.
The compounds of the formula XI can be prepared by one of the two following schemes: 
For the preparation of the compounds according to the invention in which R2 and R13 are a radical of one of [sic] the above general formula VII or together form a linkage having the general formula V, IX or X, a 2,2xe2x80x2-bis-1H-indolylalkane or a derivative thereof having the general formula XI 
in which X, R1, R3, R4, R5, R6, R7, R8, R9, R10 and R11 have the same meaning as above, is initially reacted with dibromomaleimide.
Compounds according to the invention in which R2and R13 together form a linkage having the general formula VII are then reacted with a primary or secondary amine of the following general structures [sic] XVI, XVII or piperazine 
in which p, q, R17 and W have the same meaning as above.
The following examples illustrate the invention, without restricting it.